Systematic use of protein free energy changes for classifying variants of uncertain significance: the case of IFT140 in Mainzer-Saldino Syndrome.

ABSTRACT:

Introduction

Advanced genetic strategies have transformed our understanding of the genetic basis and diagnosis of many phenotypes, including rare diseases. However, missense variants (MVs) are frequently identified and often classified as variants of uncertain significance (VUS). Although changes in protein free energy (ΔΔG) were recently proposed as a tool for VUS classification, no objective cut-offs exist to distinguish between benign and pathogenic variants.

Methods

We utilized the computational tool mCSM to calculate ΔΔG and predict the impact of MVs on protein stability. Specifically, we systematically analyzed the ΔΔG of MVs in IFT140 to identify those potentially pathogenic and associated with Mainzer-Saldino syndrome (MSS). To this end, we evaluated ΔΔG in IFT140 MV

SUBMITTER: Gajardo M 

PROVIDER: S-EPMC12055525 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature